Glycoside hydrolases (GH) are a large family of hydrolytic enzymes found in all domains of life. As such, they control a plethora of normal and pathogenic biological functions. Thus, understanding selective inhibition of GH enzymes at the atomic level can lead to the identification of new classes of therapeutics. In these studies, we identified a 4-⍺-glucoside of valienamine (8) as an inhibitor of Streptomyces coelicolor (Sco) GlgE1-V279S which belongs to the GH13 Carbohydrate Active EnZyme family. The results obtained from the dose–response experiments show that 8 at a concentration of 1000 µM reduced the enzyme activity of Sco GlgE1-V279S by 65%. The synthetic route to 8 and a closely related 4-⍺-glucoside of validamine (7) was achieved starting from readily available D-maltose. A key step in the synthesis was a chelation-controlled addition of vinylmagnesium bromide to a maltose-derived enone intermediate. X-ray structures of both 7 and 8 in complex with Sco GlgE1-V279S were solved to resolutions of 1.75 and 1.83 Å, respectively. Structural analysis revealed the valienamine derivative 8 binds the enzyme in an E2 conformation for the cyclohexene fragment. Also, the cyclohexene fragment shows a new hydrogen-bonding contact from the pseudo-diaxial C(3)–OH to the catalytic nucleophile Asp 394 at the enzyme active site. Asp 394, in fact, forms a bidentate interaction with both the C(3)–OH and C(7)-OH of the inhibitor. In contrast, compound 7 disrupts the catalytic sidechain interaction network of Sco GlgE1-V279S via steric interactions resulting in a conformation change in Asp 394. These findings will have implications for the design other aminocarbasugar-based GH13-inhibitors and will be useful for identifying more potent and selective inhibitors.
Synthesis of C-glycosylated cinnamoylfuran derivatives and their cytotoxic effects on cancer cells (MCF-7 and HeLa) and normal cells is presented.
An effective reaction condition for the rapid transformation of nitrile derivatives into thioamide derivatives has been developed by the treatment with a combination of carbon disulfide and sodium sulfide. The reaction condition is equally effective for the transformation of alkyl, aryl nitriles. C‐Glycosyl nitriles also furnished C‐glycosyl thioamide derivatives in satisfactory yield under the reported reaction condition. The reaction condition is simple, high yielding and suitable for scaled up.
Tuberculosis is a disease caused primarily by the organism Mycobacterium tuberculosis ( Mtb ), which claims about 1.5 million lives every year. A challenge that impedes the elimination of this pathogen is the ability of Mtb to remain dormant after primary infection, thus creating a reservoir for the disease in the population that reactivates under more ideal conditions. A better understanding of the physiology of dormant Mtb and therapeutics able to kill these phenotypically tolerant bacilli will be critical for completely eradicating Mtb . Our groups are focusing on characterizing the activity of derivatives of the marine natural product (+)-puupehenone ( 1 ). Recently, the Rohde group reported that puupehedione ( 2 ) and 15-α-methoxypuupehenol ( 3 ) exhibit enhanced activity in an in vitro multi-stress dormancy model of Mtb. To optimize the antimycobacterial activity of these terpenoids, novel 15-α-methoxy- and 15-α-acetoxy-puupehenol esters were prepared from (+)-puupehenone ( 1 ) accessed through a (+)-sclareolide-derived β-hydroxyl aldehyde. For added diversity, various congeners related to ( 1 ) were also prepared from a common borono-sclareolide donor, which resulted in the synthesis of epi -puupehenol and the natural products (+)-chromazonarol and (+)-yahazunol. In total, we generated a library of 24 compounds, of which 14 were found to be active against Mtb , and the most active compounds retained the enhanced activity against dormant Mtb seen in the parent compound. Several of the 15-α-methoxy- and 15-α-acetoxy-puupehenol esters possessed potent activity against actively dividing and dormant Mtb . Intriguingly, the closely related triisobutyl derivative 16 showed similar activity to 1 in actively dividing Mtb but lost about 178-fold activity against dormant Mtb . However, the monopivaloyl compound 13 showed a modest 3- to 4-fold loss in activity in both actively dividing and dormant Mtb relative to the activity of 1 revealing the importance of the free OH at C19 supporting the potential role of quinone methide formation as critical for activity in dormant Mtb . Elucidating important structure–activity relationships and the mechanism of action of this natural product-inspired chemical series may yield insights into vulnerable drug targets in dormant bacilli and new therapeutics to more effectively target dormant Mtb .
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